Phospholipid vesicles have often been acclaimed for their potential as anticancer drug delivery agents. However, there is little experimental evidence which confirms that liposomes actually target chemotherapy to solid tumors. The overall goals of this SBIR project are: 1) to verify that small vesicles with compositions which are recognized for their stability, can be loaded with selected antitumor drugs, 2) to prove that such drug loaded liposomes can increase drug uptake in experimental tumors while decreasing the level of drug in critical normal tissues, and 3) to establish that such vesicle targeting of chemotherapy can increase antitumor efficacy while decreasing the toxic side effects. During Phase I, vesicle formulations prepared from pure phospholipids and cholesterol will be loaded with doxorubicin, a drug with cardiotoxic side effects. Drug loaded liposomes and unencapsulated doxorubicin will be injected intravenously into separate sets of mice bearing solid Lewis lung carcinoma tumors. At various times after injection, blood, tumor, and heart tissue will be removed and extracted with 10 M urea, and the extract will be analyzed for doxorubicin. A high performance liquid chromatography apparatus with a sensitive fluorescence detector will be used to separate the parent drug from its metabolites. Quantitative data on the drug concentrations in each tissue will be obtained. Based on previous results with vesicle encapsulated radioisotope, tumor uptake of vesicle encapsulated drug is expected to increase, compared to concentrations attained with free drug. A two-fold or greater increase in tumor drug exposure is thought to have significant therapeutic implications. Thus, if such an increase is observed, Phase II of the project, testing toxicology and therapy of vesicles encapsulated doxorubicin will be initiated. The recognition that only the smallest vesicles, which are stable to leakage of encapsulated material while circulating in the blood, are capable of tumor targeting may lead to a renewed interest in these entities. If favorable tumor targeting can be demonstrated, this approach could have widespread health benefits and commercial applications.